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Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1.
Mol Pharmacol. 2005 Dec; 68(6):1524-33.MP

Abstract

Vanilloid receptor 1 (TRPV1) is activated by chemical ligands (e.g., capsaicin and protons) and heat. In this study, we show that (2E)-3-[2-piperidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]-N-quinolin-7-ylacrylamide (AMG6880), 5-chloro-6-[(3R)-3-methyl-4-[6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzimidazol-2-yl]piperazin-1-yl]pyridin-3-yl)methanol (AMG7472), and N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC) are potent antagonists of rat TRPV1 activation by either capsaicin or protons (pH 5) (defined here as group A antagonists), whereas (2E)-3-(6-tert-butyl-2-methylpyridin-3-yl)-N-(1H-indol-6-yl)acrylamide (AMG0610), capsazepine, and (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)acrylamide (SB-366791) are antagonists of capsaicin, but not proton, activation (defined here as group B antagonists). By using capsaicin-sensitive and insensitive rabbit TRPV1 channels, we show that antagonists require the same critical molecular determinants located in the transmembrane domain 3/4 region to block both capsaicin and proton activation, suggesting the presence of a single binding pocket. To determine whether the differential pharmacology is a result of proton activation-induced conformational changes in the capsaicin-binding pocket that alter group B antagonist affinities, we have developed a functional antagonist competition assay. We hypothesized that if group B antagonists bind at the same or an overlapping binding pocket of TRPV1 as group A antagonists, and proton activation does not alter the binding pocket, then group B antagonists should compete with and prevent group A antagonism of TRPV1 activation by protons. Indeed, we found that each of the group B antagonists competed with and prevented BCTC, AMG6880 or AMG7472 antagonism of rat TRPV1 activation by protons with pA2 values similar to those for blocking capsaicin, indicating that proton activation does not alter the conformation of the TRPV1 capsaicin-binding pocket. In conclusion, group A antagonists seem to lock the channel conformation in the closed state, blocking both capsaicin and proton activation.

Authors+Show Affiliations

Department of Neuroscience, Amgen Inc., MS-29-2-B, One Amgen Center Dr., Thousand Oaks, California 91320-1799, USA. ngavva@amgen.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16135784

Citation

Gavva, Narender R., et al. "Proton Activation Does Not Alter Antagonist Interaction With the Capsaicin-binding Pocket of TRPV1." Molecular Pharmacology, vol. 68, no. 6, 2005, pp. 1524-33.
Gavva NR, Tamir R, Klionsky L, et al. Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. Mol Pharmacol. 2005;68(6):1524-33.
Gavva, N. R., Tamir, R., Klionsky, L., Norman, M. H., Louis, J. C., Wild, K. D., & Treanor, J. J. (2005). Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. Molecular Pharmacology, 68(6), 1524-33.
Gavva NR, et al. Proton Activation Does Not Alter Antagonist Interaction With the Capsaicin-binding Pocket of TRPV1. Mol Pharmacol. 2005;68(6):1524-33. PubMed PMID: 16135784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. AU - Gavva,Narender R, AU - Tamir,Rami, AU - Klionsky,Lana, AU - Norman,Mark H, AU - Louis,Jean-Claude, AU - Wild,Kenneth D, AU - Treanor,James J S, Y1 - 2005/08/31/ PY - 2005/9/2/pubmed PY - 2006/1/20/medline PY - 2005/9/2/entrez SP - 1524 EP - 33 JF - Molecular pharmacology JO - Mol Pharmacol VL - 68 IS - 6 N2 - Vanilloid receptor 1 (TRPV1) is activated by chemical ligands (e.g., capsaicin and protons) and heat. In this study, we show that (2E)-3-[2-piperidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]-N-quinolin-7-ylacrylamide (AMG6880), 5-chloro-6-[(3R)-3-methyl-4-[6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzimidazol-2-yl]piperazin-1-yl]pyridin-3-yl)methanol (AMG7472), and N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC) are potent antagonists of rat TRPV1 activation by either capsaicin or protons (pH 5) (defined here as group A antagonists), whereas (2E)-3-(6-tert-butyl-2-methylpyridin-3-yl)-N-(1H-indol-6-yl)acrylamide (AMG0610), capsazepine, and (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)acrylamide (SB-366791) are antagonists of capsaicin, but not proton, activation (defined here as group B antagonists). By using capsaicin-sensitive and insensitive rabbit TRPV1 channels, we show that antagonists require the same critical molecular determinants located in the transmembrane domain 3/4 region to block both capsaicin and proton activation, suggesting the presence of a single binding pocket. To determine whether the differential pharmacology is a result of proton activation-induced conformational changes in the capsaicin-binding pocket that alter group B antagonist affinities, we have developed a functional antagonist competition assay. We hypothesized that if group B antagonists bind at the same or an overlapping binding pocket of TRPV1 as group A antagonists, and proton activation does not alter the binding pocket, then group B antagonists should compete with and prevent group A antagonism of TRPV1 activation by protons. Indeed, we found that each of the group B antagonists competed with and prevented BCTC, AMG6880 or AMG7472 antagonism of rat TRPV1 activation by protons with pA2 values similar to those for blocking capsaicin, indicating that proton activation does not alter the conformation of the TRPV1 capsaicin-binding pocket. In conclusion, group A antagonists seem to lock the channel conformation in the closed state, blocking both capsaicin and proton activation. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16135784/Proton_activation_does_not_alter_antagonist_interaction_with_the_capsaicin_binding_pocket_of_TRPV1_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16135784 DB - PRIME DP - Unbound Medicine ER -